The two main protocols for this project have been approved and are in active recruitment and accrual stages now. We continue to enroll a cohort of patients with severe atopic dermatitis (AD) alone, and those with AD in the context of immune deficiency. We have a substantial cohort of patients with genetic disorders, which include atopy as a part of the syndrome (now numbering over 200 patients total). Three main findings have occurred in this project within the past year, describted in detail below. Finding 1: In order to assess the effects of STAT3 mutations on allergic disease, we performed detailed allergic histories on the majority of the NIH AD-HIES (autosomal dominant hyper-IgE syndrome)cohort and compared them to patients with marked IgE elevations but no STAT3 mutation. Patients with HIES had a substantially lower incidence of food allergy, asthma and anaphylaxis compared to those with similarly elevated IgE levels. Allergen-specific IgE was measured using ImmunoCap RAST and prominent allergen-specific IgE was measured in most patients, arguing against a defect in antibody specificity. Foxp3+ regulatory T cells (Tregs) have been shown to directly inhibit mast cell function, and many models of experimental atopy can be suppressed with regulatory T cells. We enumerated Foxp3+ T cells in HIES patients and found that within the diminished central memory compartment, there is a marked enrichment of Tregs compared to control. We have also shown that the defect appears primarily to be in mast cells, as STAT3 knockdown of human mast cells leads to marked reduction in the capacity for degranulation, and to a proximal signaling defect. Using a mouse model of AD-HIES in collaboration with Drs. Juan Rivera and John O'Shea's labs (NIAMS) we found that systemic IgE crosslinking or addition of mast cell secretagogue leads to impaired anaphylaxis in AD-HIES mice compared to controls. We have therefore identified STAT3 as a critical mediator of acute mast cell degranulation via the study of allergic disease in this rare immune deficiency. This report was published in the Journal of Allergy and Clinical Immunology. Finding 2: Wet-wrap therapy is a mainstay of care for our patients with severe atopic dermatitis regardless of underlying etiology. We have now performed this therapy on over 50 patients refractory to the outpatient standard of care. We have found that while there is a transient drop in morning cortisol levels, this recovers, and there are few short or long term adverse affects of this therapy up to 2 years of follow up. We also found that there is an acute drop in circulating eosinophils, which recovers slightly, but then remains low up to two years of follow up. The long-term improvement in objective rash burden as well as subjective quality of life measures is quite significant (nearly 50% for all) and never before observed for such a prolonged follow up period in such a diverse patient group-- 1-2 years. In addition, we have performed this procedure on a variety of different immune deficiencies, including Chronic Granulomatous Disease, Dock8 deficiency, PGM3 deficiency and STAT3 deficiency. Our success in those patients has both demonstrated the safety and the utility of the wraps in those conditions. A manuscript describing these findings is in preparation